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Cardiotoxicity Assessment through a Polymer-Based Cantilever Platform: An Integrated Electro-Mechanical Screening
Pooja P Kanade1,2, Nomin-Erdene Oyunbaatar1,2, Jongyun Kim1,2
1School of Mechanical Engineering, Chonnam National University, Gwangju, 61186, South Korea.
Abstract:
Preclinical drug screening for cardiac toxicity has traditionally relied on observing changes in cardiomyocytes' electrical activity, primarily through invasive patch clamp techniques or non-invasive microelectrode arrays (MEA). However, relying solely on field potential duration (FPD) measurements for electrophysiological assessment can miss the full spectrum of drug-induced toxicity, as different drugs affect cardiomyocytes through various mechanisms. A more comprehensive approach, combining field potential and contractility measurements, is essential for accurate toxicity profiling, particularly for drugs targeting contractile proteins without affecting electrophysiology. However, previously proposed platform has significant limitations in terms of simultaneous measurement. The novel platform addresses these issues, offering enhanced, non-invasive evaluation of drug-induced cardiotoxicity. It features eight cantilevers with patterned strain sensors and MEA, enabling real-time monitoring of both cardiomyocyte contraction force and field potential. This system can detect minimum cardiac contraction force of ≈2 µN and field potential signals with 50 µm MEA diameter, using the same cardiomyocytes in measurements of two parameters. Testing with six drugs of varied mechanisms of action, the platform successfully identifies these mechanisms and accurately assesses toxicity profiles, including drugs not inhibiting potassium channels. This innovative approach presents a comprehensive, non-invasive method for cardiac function assessment, poised to revolutionize preclinical cardiotoxicity screening.
Insights
This study introduces a novel platform for assessing drug-induced cardiotoxicity by simultaneously measuring cardiomyocyte electrical activity and contraction force. This comprehensive approach improves preclinical drug screening accuracy for cardiac safety.
Area of Science:
- Cardiovascular Research
- Drug Discovery and Development
- Biomedical Engineering
Background:
- Traditional preclinical cardiac toxicity screening relies on electrophysiology (e.g., microelectrode arrays - MEA), which may not capture all drug effects.
- Assessing only field potential duration (FPD) is insufficient as drugs have diverse mechanisms of action.
- Existing platforms lack simultaneous measurement of both electrophysiology and contractility.
Purpose of the Study:
- To develop and validate a novel, non-invasive platform for comprehensive preclinical cardiotoxicity evaluation.
- To enable simultaneous real-time monitoring of cardiomyocyte electrical activity and contraction force.
- To improve the accuracy of cardiac safety profiling for diverse drug mechanisms.
Main Methods:
- A novel platform featuring eight cantilevers with strain sensors and MEA for simultaneous measurement.
- Real-time monitoring of cardiomyocyte contraction force (detecting ≈2 µN) and field potential signals.
- Utilizing the same cardiomyocytes for both electrophysiological and contractility measurements.
Main Results:
- The platform successfully detected drug-induced toxicity profiles for six drugs with varied mechanisms.
- It accurately identified toxicity even for drugs not affecting potassium channels.
- Demonstrated capability for sensitive detection of cardiac contraction force and field potential.
Conclusions:
- The developed platform offers a comprehensive, non-invasive method for assessing drug-induced cardiotoxicity.
- This innovative approach enhances preclinical cardiac function assessment.
- Poised to significantly advance the field of preclinical cardiotoxicity screening.
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